U.S. patent application number 09/950436 was filed with the patent office on 2002-08-01 for methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure.
Invention is credited to Cormier, Michel, Daddona, Peter, Johnson, Juanita, Lin, Wei Qi, Matriano, James.
Application Number | 20020102292 09/950436 |
Document ID | / |
Family ID | 22867983 |
Filed Date | 2002-08-01 |
United States Patent
Application |
20020102292 |
Kind Code |
A1 |
Cormier, Michel ; et
al. |
August 1, 2002 |
Methods for inhibiting decrease in transdermal drug flux by
inhibition of pathway closure
Abstract
This invention relates to a method for inhibiting a decrease in
the transdermal flux of an agent that is being transdermally
delivered or sampled over a prolonged period of time wherein the
delivery or sampling involves disrupting at least the stratum
corneum layer of the skin to form pathways through which the agent
passes. The desired result is achieved by co-delivering or
co-sampling the agent with an amount of at least one anti-healing
agent wherein the amount of the anti-healing agent is effective in
inhibiting a decrease in the agent transdermal flux compared to
when the delivery or sampling of the agent is done under
substantially identical conditions except in the absence of the
anti-healing agent(s).
Inventors: |
Cormier, Michel; (Mountain
View, CA) ; Johnson, Juanita; (Belmont, CA) ;
Lin, Wei Qi; (Palo Alto, CA) ; Matriano, James;
(Mountain View, CA) ; Daddona, Peter; (Menlo Park,
CA) |
Correspondence
Address: |
ALZA Corporation
1900 Charleston Road
M10-3
P.O. Box 7210
Mountain View
CA
94039-7210
US
|
Family ID: |
22867983 |
Appl. No.: |
09/950436 |
Filed: |
September 8, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60231160 |
Sep 8, 2000 |
|
|
|
Current U.S.
Class: |
424/449 ; 514/54;
514/56; 514/566; 514/574; 514/59 |
Current CPC
Class: |
A61K 9/703 20130101;
A61K 9/0021 20130101; Y10S 514/947 20130101; A61K 9/7084
20130101 |
Class at
Publication: |
424/449 ; 514/54;
514/56; 514/59; 514/566; 514/574 |
International
Class: |
A61K 009/70; A61K
031/737; A61K 031/727; A61K 031/721; A61K 031/195; A61K 031/19 |
Claims
What is claimed is:
1. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming one or more
disruptions in at least the stratum corneum layer of the skin to
form one ore more pathways; and causing the first agent and at
least one anti-healing agent to be fluxed through said one or more
pathways, wherein the amount of said at least one anti-healing
agent that is fluxed through said one or more pathways is effective
in inhibiting the decrease in the transdermal flux of said first
agent compared to the flux of said first agent under substantially
identical conditions except in the absence of said at least one
anti-healing agent.
2. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming microslits in at least
the stratum corneum layer of the skin by the application of
stratum-corneum-piercing microprotrusions to the skin to form one
or more pathways through which said first agent passes; and causing
the first agent and at least one anti-healing agent to be fluxed
through said one or more pathways, wherein the amount of said at
least one anti-healing agent that is fluxed through said pathways
is effective in inhibiting the decrease in the transdermal flux of
said first agent compared to the flux of said first agent under
substantially identical conditions except in the absence of said at
least one anti-healing agent.
3. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and wherein said anti-healing agent is selected from the
group consisting of anticoagulants, anti-inflammatory agents,
agents that inhibit cellular migration, and osmotic agents and
mixtures thereof.
4. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and said anti-healing agent comprises an agent selected from
the group consisting of anticoagulants, anti-inflammatory agents,
agents that inhibit cellular migration, and osmotic agents and
mixtures thereof; and wherein said anticoagulants are selected from
the group consisting of heparin having a molecular weight from 3000
to 12,000 daltons, pentosan polysulfate, citric acid, citrate
salts, EDTA, and dextrans having molecular weight from 2000 to
10,000 daltons, aspirin and lyapolate sodium.
5. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and said anti-healing agent comprises an agent selected from
the group consisting of anticoagulants, anti-inflammatory agents,
agents that inhibit cellular migration, and osmotic agents and
mixtures thereof; and wherein said anti-inflammatory agent is
selected from the group consisting of hydrocortisone sodium
phosphate, betamethasone sodium phosphate, and triamcinolone sodium
phosphate.
6. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and said anti-healing agent comprises an agent selected from
the group consisting of anticoagulants, anti-inflammatory agents,
agents that inhibit cellular migration, and osmotic agents and
mixtures thereof; and wherein said anti-healing agent that inhibits
cellular migration is laminin.
7. A method for inhibiting a decrease in transdermal flux of a
first agent being delivered or sampled comprising the steps of:
forming disruptions in at least the stratum corneum layer of the
skin to form one or more pathways; causing the first agent and at
least one anti-healing agent to be fluxed through said one or more
pathways, wherein the amount of said at least one anti-healing
agent that is fluxed through said one or more pathways is effective
in inhibiting the decrease in the transdermal flux of said first
agent compared to the flux of said first agent under substantially
identical conditions except in the absence of said at least one
anti-healing agent; said anti-healing agent comprises an agent
selected from the group consisting of anticoagulants,
anti-inflammatory agents, agents that inhibit cellular migration,
and osmotic agents and mixtures thereof; and wherein said osmotic
agent is a biologically compatible salt of an osmotic agent.
8. A method for inhibiting a decrease in transdermal flux of a
first agent being delivered or sampled comprising the steps of:
forming disruptions in at least the stratum corneum layer of the
skin to form one or more pathways; causing the first agent and at
least one anti-healing agent to be fluxed through said one or more
pathways, wherein the amount of said at least one anti-healing
agent that is fluxed through said one or more pathways is effective
in inhibiting the decrease in the transdermal flux of said first
agent compared to the flux of said first agent under substantially
identical conditions except in the absence of said at least one
anti-healing agent; said anti-healing agent comprises an agent
selected from the group consisting of anticoagulants,
anti-inflammatory agents, agents that inhibit cellular migration,
and osmotic agents and mixtures thereof; and wherein said osmotic
agent generates an osmotic pressure greater than about 2000
kilo-pascals at 20.degree. C.
9. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form a one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and wherein said first agent is a therapeutic agent which is
delivered into the skin.
10. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and wherein said first agent is a macromolecular therapeutic
agent.
11. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and wherein said first agent is a macromolecular therapeutic
agent selected from the group consisting of polypeptides, proteins,
oligonucleotides, nucleic acids and polysaccharides.
12. A method for inhibiting a decrease in transdermal flux of a
therapeutic agent comprising the steps of: forming disruptions in
at least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways by placing a
reservoir in agent transmitting relation with the disruptions in at
least the stratum corneum, said reservoir comprising the first
agent and the at least one anti-healing agent, wherein the amount
of said anti-healing agent that is fluxed through said one or more
pathways is effective in inhibiting the decrease in the transdermal
flux of said first agent compared to the flux of said first agent
under substantially identical conditions except in the absence of
said at least one anti-healing agent; and wherein said first agent
is a therapeutic agent.
13. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form a one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and wherein the first agent is a body analyte that is
transdermally sampled.
14. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and wherein the first agent is the body analyte glucose that
is transdermally sampled.
15. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways by placing a
reservoir in agent transmitting relation with the disruptions in at
least the stratum corneum, said reservoir comprising the first
agent and the at least one anti-healing agent, wherein the amount
of said anti-healing agent that is fluxed through said one or more
pathways is effective in inhibiting the decrease in the transdermal
flux of said first agent compared to the flux of said first agent
under substantially identical conditions except in the absence of
said at least one anti-healing agent; and wherein the first agent
is a body analyte that is transdermally sampled.
16. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form a plurality of
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and wherein the anti-healing agent is fully or partially
delivered before, during, or after transdermal flux of the first
agent.
17. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming one or more microslits
in at least the stratum corneum layer of the skin by the
application of stratum-corneum-piercing microprotrusions to the
skin to form one or more pathways; said microprotrusions having a
length of less than about 0.019685 inches (0.5 millimeters); and
causing the first agent and at least one anti-healing agent to be
fluxed through said one or more pathways, wherein the amount of
said at least one anti-healing agent that is fluxed through said
one or more pathways is effective in inhibiting the decrease in the
transdermal flux of said first agent compared to the flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent; and
18. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; and causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and said first agent being a body analyte that is
transdermally sampled, and wherein said one or more
microprotrusions and said reservoir are a single integral
element.
19. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and wherein the first agent is an anti-healing agent
selected from the group consisting of heparin having a molecular
weight from 3000 to 12,000 daltons, pentosan polysulfate, citric
acid, citrate salts, EDTA, and dextrans having molecular weight
from 2000 to 10,000 daltons.
20. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; said anti-healing agent selected from the group consisting
of heparin having a molecular weight from 3000 to 12,000 daltons,
pentosan polysulfate, citric acid, citrate salts, EDTA, and
dextrans having molecular weight from 2000 to 10,000 daltons, and
wherein the first agent and the anti-healing agent are the same
agent.
21. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming disruptions in at
least the stratum corneum layer of the skin to form one or more
pathways; causing the first agent and at least one anti-healing
agent to be fluxed through said one or more pathways, wherein the
amount of said at least one anti-healing agent that is fluxed
through said one or more pathways is effective in inhibiting the
decrease in the transdermal flux of said first agent compared to
the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and wherein said anti-healing agent is selected from the
group consisting of anticoagulants, anti-inflammatory agents,
agents that inhibit cellular migration, and neutral osmotic agents
and mixtures thereof.
22. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming one or more microslits
in at least the stratum corneum layer of the skin by the
application of one or more stratum-corneum-piercing
microprotrusions to the skin to form one or more pathways; forming
a dry coating of said first agent and at least one anti-healing
agent on one or more of said microprotrusions; and causing the
first agent and said at least one anti-healing agent to be fluxed
through said one or more pathways, wherein the amount of said at
least one anti-healing agent that is fluxed through said one or
more pathways is effective in inhibiting the decrease in the
transdermal flux of said first agent compared to the flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent.
23. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming one or more microslits
in at least the stratum corneum layer of the skin by the
application of one or more stratum-corneum-piercing
microprotrusions to the skin to form one or more pathways; forming
a dry coating of said first agent on one or more of said
microprotrusions; causing the first agent and at least one
anti-healing agent to be fluxed through said one or more pathways,
wherein the amount of said at least one anti-healing agent that is
fluxed through said one or more pathways is effective in inhibiting
the decrease in the transdermal flux of said first agent compared
to the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and wherein the first agent is a therapeutic agent delivered
transdermally through the skin.
24. A method for inhibiting a decrease in transdermal flux of a
first agent comprising the steps of: forming one or more microslits
in at least the stratum corneum layer of the skin by the
application of one or more stratum-corneum-piercing
microprotrusions to the skin to form one or more pathways; placing
a separate reservoir in agent transmitting relation with the skin,
said separate reservoir comprising at least one anti-healing agent,
forming a dry coating of said first agent on one or more of said
microprotrusions; causing the first agent and at least one
anti-healing agent to be fluxed through said one or more pathways,
wherein the amount of said at least one anti-healing agent that is
fluxed through said one or more pathways is effective in inhibiting
the decrease in the transdermal flux of said first agent compared
to the flux of said first agent under substantially identical
conditions except in the absence of said at least one anti-healing
agent; and wherein the first agent is a therapeutic agent delivered
transdermally through the skin.
25. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent.
26. A device for causing the transdermal flux of an agent
comprising: a first element comprising one or more stratum corneum
piercing microprotrusion which are capable of forming microslits in
at least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent.
27. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent, and wherein the
anti-healing agent is selected from the group consisting of
anticoagulants, anti-inflammatory agents, agents that inhibit
cellular migration, and osmotic agents and mixtures thereof.
28. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent, said anti-healing
agent is selected from the group consisting of anticoagulants,
anti-inflammatory agents, agents that inhibit cellular migration,
and osmotic agents and mixtures thereof and wherein said
anticoagulant is selected from the group consisting of heparin
having a molecular weight from 3000 to 12,000 daltons, pentosan
polysulfate, citric acid, citrate salts, EDTA, and dextrans having
molecular weight from 2000 to 10,000 daltons, aspirin and lyapolate
sodium.
29. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent, wherein the
anti-healing agent is selected from the group consisting of
anticoagulants, anti-inflammatory agents, agents that inhibit
cellular migration, and osmotic agents and mixtures thereof; and
wherein said anti-inflammatory agent is selected from the group
consisting of hydrocortisone sodium phosphate, betamethasone sodium
phosphate, and triamcinolone sodium phosphate.
30. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent, wherein the
anti-healing agent is selected from the group consisting of
anticoagulants, anti-inflammatory agents, agents that inhibit
cellular migration, and osmotic agents and mixtures thereof; and
wherein the agent that inhibits cellular migration is laminin.
31. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent, wherein the
anti-healing agent is selected from the group consisting of
anticoagulants, anti-inflammatory agents, agents that inhibit
cellular migration, and osmotic agents and mixtures thereof; and
wherein said osmotic agent is a biologically compatible salt of an
osmotic agent.
32. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent, wherein said
anti-healing agent is selected from the group consisting of
anticoagulants, anti-inflammatory agents, agents that inhibit
cellular migration, and osmotic agents and mixtures thereof; and
wherein said osmotic agent, in solution, generates an osmotic
pressure greater than about 2,000 kilopascals at 20.degree. C.
33. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent; and wherein the
first agent is a therapeutic agent and said device delivers said
therapeutic agent transdermally into the skin.
34. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent; and wherein the
first agent is a therapeutic agent and said device delivers said
therapeutic agent transdermally into the skin, and wherein the
agent comprises a macromolecular agent.
35. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent; and wherein the
first agent is a therapeutic agent and said device delivers said
therapeutic agent transdermally into the skin, and wherein the
macromolecular agent is selected from the group consisting of
polypeptides, proteins, oligonucleotides, nucleic acids and
polysaccharides.
36. A device for causing the transdermal flux of an agent
comprising: a first element comprising one or more stratum
corneum-piercing microprotrusions which are capable of disrupting
the skin by the formation of microslits in the stratum corneum of
the skin in order to form pathways therethrough; and at least one
reservoir comprising a first agent and at least one anti-healing
agent, said at least one reservoir is capable of being placed in
agent transmitting relationship with the skin and said pathways,
wherein the amount of said at least one anti-healing agent is
effective in inhibiting a decrease in agent transdermal flux when
compared to the transdermal flux of said first agent under
substantially identical conditions except in the absence of said at
least one anti-healing agent; and wherein the first agent is a
therapeutic agent and said device delivers said therapeutic agent
transdermally into the skin.
37. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent; and wherein the
first agent is a body analyte that is transdermally sampled.
38. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent; and wherein the
first agent is the body analyte glucose that is transdermally
sampled.
39. A device for causing the transdermal flux of an agent
comprising: a first element comprising one or more stratum
corneum-piercing microprotrusions which are capable of disrupting
the skin by the formation of one or more microslits in the stratum
corneum of the skin which form one or more pathways therethrough;
and at least one reservoir comprising a first agent and at least
one anti-healing agent, said at least one reservoir is capable of
being placed in agent transmitting relationship with the skin and
said pathways, wherein the amount of said at least one anti-healing
agent is effective in inhibiting a decrease in agent transdermal
flux when compared to the transdermal flux of said first agent
under substantially identical conditions except in the absence of
said at least one anti-healing agent; and wherein the first agent
is a body analyte that is transdermally sampled.
40. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent; and wherein the
anti-healing agent is delivered: (a) before any transdermal flux of
the first agent; (b) before and during transdermal flux of the
first agent; (c) during transdermal flux of the first agent; or (d)
during and after transdermal flux of the first agent.
41. A device for causing the transdermal flux of an agent
comprising: a first element comprising one or more stratum corneum
piercing microprotrusion which are capable of forming microslits in
at least the stratum corneum of the skin in order to form pathways
therethrough; said microprotrusion having a length of less than 0.5
mm; and at least one reservoir comprising a first agent and at
least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent.
42. A device for causing the transdermal flux of an agent
comprising: a first element comprising one or more stratum
corneum-piercing microprotrusions which are capable of disrupting
the skin by the formation of one or more microslits in the stratum
corneum of the skin which form one or more pathways therethrough;
and at least one reservoir comprising a first agent and at least
one anti-healing agent, said at least one reservoir is capable of
being placed in agent transmitting relationship with the skin and
said pathways, wherein the amount of said at least one anti-healing
agent is effective in inhibiting a decrease in agent transdermal
flux when compared to the transdermal flux of said first agent
under substantially identical conditions except in the absence of
said at least one anti-healing agent; and wherein the first agent
is a body analyte that is transdermally sampled; and wherein the
microprotrusions and the reservoir are an integral element.
43. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent; and wherein the
first agent is selected from the group consisting of heparin having
a molecular weight from 3000 to 12,000 daltons, pentosan
polysulfate, citric acid, citrate salts, EDTA, and dextrans having
molecular weight from 2000 to 10,000 daltons.
44. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent; and wherein the
first agent and the anti-healing agent are the same compound and
selected from the group consisting of heparin having a molecular
weight from 3000 to 12,000 daltons, pentosan polysulfate, citric
acid, citrate salts, EDTA, and dextrans having molecular weight
from 2000 to 10,000 daltons.
45. A device for causing the transdermal flux of an agent
comprising: a first element capable of forming disruptions in at
least the stratum corneum of the skin in order to form pathways
therethrough; and at least one reservoir comprising a first agent
and at least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent, and wherein the
anti-healing agent is selected from the group consisting of
anticoagulants, anti-inflammatory agents, agents that inhibit
cellular migration, and neutral osmotic agents and mixtures
thereof.
46. A device for causing the transdermal flux of an agent
comprising: a first element comprising one or more stratum corneum
piercing microprotrusion which are capable of forming microslits in
at least the stratum corneum of the skin in order to form pathways
therethrough; said first agent and said at least one anti-healing
agent are dry-coated on said one or more microprotrusions; and
wherein the amount of said at least one anti-healing agent is
effective in inhibiting a decrease in agent transdermal flux when
compared to the transdermal flux of said first agent under
substantially identical conditions except in the absence of said at
least one anti-healing agent.
47. A device for causing the transdermal flux of an agent
comprising: a first element comprising one or more stratum corneum
piercing microprotrusion which are capable of forming microslits in
at least the stratum corneum of the skin in order to form pathways
therethrough, wherein the first agent is a therapeutic agent dry
coated on one or more of said microprotrusions, wherein said device
is capable of delivering said first agent transdermally into the
skin, and at least one reservoir comprising a first agent and at
least one anti-healing agent, said at least one reservoir is
capable of being placed in agent transmitting relationship with the
skin and said pathways, wherein the amount of said at least one
anti-healing agent is effective in inhibiting a decrease in agent
transdermal flux when compared to the transdermal flux of said
first agent under substantially identical conditions except in the
absence of said at least one anti-healing agent.
48. A device for causing the transdermal flux of an agent
comprising: a first element comprising one or more stratum corneum
piercing microprotrusion which are capable of forming microslits in
at least the stratum corneum of the skin in order to form pathways
therethrough, wherein the first agent is a therapeutic agent dry
coated on one or more of said microprotrusions, wherein said device
is capable of delivering said first agent transdermally into the
skin, and at least one reservoir comprising at least one
anti-healing agent, said at least one reservoir is capable of being
placed in agent transmitting relationship with the skin and said
pathways, wherein the amount of said at least one anti-healing
agent is effective in inhibiting a decrease in agent transdermal
flux when compared to the transdermal flux of said first agent
under substantially identical conditions except in the absence of
said at least one anti-healing agent.
49. A kit for the application of a device for causing the
transdermal flux of an agent comprising: the device of claim 25,
and an applicator for placing said first element of said device
onto the skin in order to form said disruptions.
Description
TECHNICAL FIELD
[0001] This invention relates to inhibiting a decrease in the
transdermal flux of an agent by inhibiting pathway closure. In
particular this invention relates to a method for inhibiting a
decrease in the transdermal flux of an agent that is being
transdermally delivered or sampled over a prolonged period of time
wherein the delivery or sampling involves disrupting at least the
stratum corneum layer of the skin to form pathways through which
the agent passes by co-delivering or co-sampling the agent with an
amount of at least one anti-healing agent wherein the amount of the
anti-healing agent is effective in inhibiting a decrease in the
agent transdermal flux compared to when the delivery or sampling of
the agent is done under substantially identical conditions except
in the absence of the anti-healing agent(s).
BACKGROUND ART
[0002] Drugs are most conventionally administered either orally or
by injection. Unfortunately, many medicaments are completely
ineffective or of radically reduced efficacy when orally
administered since they either are not absorbed or are adversely
affected before entering the blood stream and thus do not possess
the desired activity. On the other hand, the direct injection of
the medicament into the blood stream, while assuring no
modification of the medicament in administration, is a difficult,
inconvenient and uncomfortable procedure, sometimes resulting in
poor patient compliance. Transdermal drug delivery offers
improvements in these areas. However, in many instances, the rate
of delivery or flux of many agents via the passive transdermal flux
is too limited to be therapeutically effective.
[0003] One method of increasing the transdermal flux of agents
relies on the application of an electric current across the body
surface referred to as "electrotransport." "Electrotransport"
refers generally to the passage of a beneficial agent, e.g., a drug
or drug precursor, through a body surface, such as skin, mucous
membranes, nails, and the like where the agent is induced or
enhanced by the application of an electrical potential. The
electrotransport of agents through a body surface may be attained
in various manners. One widely used electrotransport process,
iontophoresis, involves the electrically induced transport of
charged ions. Electroosmosis, another type of electrotransport
process, involves the movement of a solvent with the agent through
a membrane under the influence of an electric field.
Electroporation, still another type of electrotransport, involves
the passage of an agent through pores formed by applying a high
voltage electrical pulse(s) to a membrane. In many instances, more
than one of these processes may be occurring simultaneously to a
different extent. Accordingly, the term "electrotransport" is given
herein its broadest possible interpretation, to include the
electrically induced or enhanced transport of at least one charged
or uncharged agent, or mixtures thereof, regardless of the specific
mechanism or mechanisms by which the agent is actually being
transported. Electrotransport delivery generally increases agent
flux during transdermal delivery.
[0004] Another method of increasing the agent flux involves
pre-treating the skin with, or co-delivering with the beneficial
agent, a skin permeation enhancer. A permeation enhancer substance,
when applied to a body surface through which the agent is
delivered, enhances its flux therethrough such as by increasing the
permselectivity and/or permeability of the body surface, creating
hydrophilic pathways through the body surface, and/or reducing the
degradation of the agent during transport. This methodology is
typically used when the drug is delivered transdermally by passive
diffusion.
[0005] There also have been many attempts to mechanically penetrate
or disrupt the skin thereby creating pathways into the skin in
order to enhance the transdermal flux. Some of the earliest
attempts to enhance transdermal drug flux involved abrading the
skin (e.g., with sandpaper) or tape-stripping the skin to disrupt
the stratum corneum. More recently, there have been attempts to
pierce or cut through the stratum corneum with tiny
piercing/cutting elements. See for example, U.S. Pat. Nos.
5,879,326 issued to Godshall, et al., 3,814,097 issued to
Ganderton, et al., 5,279,544 issued to Gross, et al., 5,250,023
issued to Lee, et al., 3,964,482 issued to Gerstel, et al., Reissue
25,637 issued to Kravitz, et al., and PCT Publication Nos. WO
96/37155, WO 96/37256, WO 96/17648, WO 97/03718, WO 98/11937, WO
98/00193, WO 97/48440, WO 97/48441, WO 97/48442, WO 98/00193, WO
99/64580, WO 98/28037, WO 98/29298 and WO 98/29365. These devices
use piercing elements of various shapes and sizes to pierce the
outermost layer (i.e., the stratum corneum) of the skin. The
piercing elements disclosed in these references generally extend
perpendicularly from a thin, flat member, such as a pad or sheet.
The piercing elements or microprotrusion in some of these devices
are extremely small, some having dimensions (i.e., length and
width) of only about 25-400 .mu.m and a microprotrusion thickness
of only about 5-50 .mu.m. These tiny piercing/cutting elements make
correspondingly small microslits/microcuts in the stratum corneum
for enhanced transdermal agent delivery therethrough.
[0006] It has now been discovered that in the case of human skin,
the pathways created by the microslits/microcuts are quickly closed
and sealed by the skin's natural healing processes. Although this
process is not completely understood at this time, it is believed
that it is closely related to wound healing. Wound healing is a
complex phenomenon involving many biological processes. The
earliest event, taking place within minutes, in the wound healing
process is the formation of a fibrin clot. In addition, many
pro-inflammation mediators are liberated or generated during the
early phase of wound healing. Liberation of these factors triggers
keratinocyte migration, leukocyte infiltration, fibroblast
proliferation which result in protein degradation, protein
synthesis and tissue remodeling. In the end, reformation of the
skin barrier is achieved. In some instances, the enhancement in
transdermal agent flux provided by these pathways is completely
eliminated within several hours of making the pathways. Thus, there
is a need for a method which can prevent, or at least delay the
skin's natural healing processes in order to allow transdermal flux
of agents, through microcuts/microslits over longer periods of time
(e.g., longer than about one hour) when the delivery methodology
utilizes micropiercing elements.
[0007] The present invention fulfills this and related needs.
DISCLOSURE OF THE INVENTION
[0008] This invention is directed to a method for inhibiting a
decrease in the transdermal flux of an agent which is being
transdermally delivered or sampled over a prolonged period of time
where the transdermal flux involves disrupting at least the stratum
corneum layer of the skin. Specifically, it has been discovered
that by co-delivering or co-sampling the agent in the presence of
an anti-healing agent the closure of the pathways in the skin
formed as a result of disrupting the stratum corneum layer of the
skin can be inhibited, thereby inhibiting a decrease in the
transdermal flux of the agent.
[0009] Accordingly, in a first aspect, this invention is directed
to a method for inhibiting a decrease in the transdermal flux of an
agent being transdermally delivered or sampled over a prolonged
period of time wherein the delivery involves disrupting (e.g., by
puncturing) at least the stratum corneum layer of the skin to form
a plurality of pathways through which the agent passes which method
comprises co-delivering or co-sampling the agent with an amount of
at least one anti-healing agent wherein said amount of said
anti-healing agent is effective in inhibiting a decrease in said
agent transdermal flux compared to delivering or sampling said
agent under substantially identical conditions except in the
absence of said anti-healing agent(s).
[0010] In a second aspect, this invention is directed to a method
for transdermally delivering an agent over a prolonged period of
time which method comprises:
[0011] (i) forming a plurality of micro-disruptions through the
stratum corneum layer of the skin to form pathways through which
the agent passes; and
[0012] (ii) placing a reservoir in agent transmitting relation with
the micro-disruptions formed in step (i) said reservoir comprising
the agent and an amount of at least one anti-healing agent wherein
said amount of said anti-healing agent is effective in inhibiting
the decrease in said agent transdermal flux compared to delivering
said agent under substantially identical conditions except in the
absence of said anti-healing agent(s).
[0013] In a third aspect, this invention is directed to a method
for transdermally sampling an agent over a prolonged period of time
which method comprises:
[0014] (i) forming a plurality of micro-disruptions through the
stratum corneum layer of the skin to form pathways through which
the agent passes; and
[0015] (ii) placing a reservoir in agent transmitting relation with
the micro-disruptions formed in step (i) said reservoir comprising
an amount of at least one anti-healing agent wherein said amount of
said anti-healing agent is effective in inhibiting the decrease in
said agent transdermal flux compared to sampling said agent under
substantially identical conditions except in the absence of said
anti-healing agent(s).
[0016] In the above methods, at least the stratum corneum layer of
the skin is pierced, cut or otherwise disrupted (e.g., by abrasives
or tape stripping) and most preferably at least the stratum corneum
layer of the skin is perforated with a skin perforating device
having a plurality of microprotrusions which can penetrate the
stratum corneum of the skin to form a plurality of pathways through
which the agent and the anti-healing agent pass. The anti-healing
agent(s) is delivered either before the agent is delivered or
sampled; or before and during the transdermal flux of the agent; or
during the transdermal flux of the agent; or during and after the
transdermal flux of the agent.
[0017] In the above methods, preferably, the anti-healing agent(s)
is selected from the group consisting of anticoagulants,
anti-inflammatory agents, agents that inhibit cellular migration,
and osmotic agents in an amount effective to generate, in solution,
an osmotic pressure greater than about 2000 kilopascals, preferably
greater than about 3000 kilopascals at 20.degree. C. or mixtures
thereof.
[0018] Preferably, the anticoagulant is selected from the group
consisting of heparin having a molecular weight from 3000 to 12,000
daltons, pentosan polysulfate, citric acid, citrate salts, EDTA,
and dextrans having a molecular weight from 2000 to 10,000
daltons.
[0019] Preferably the anti-inflammatory agent is selected from the
group consisting of hydrocortisone sodium phosphate, betamethasone
sodium phosphate, and triamcinolone sodium phosphate.
[0020] Preferably, the agent that inhibits the cellular migration
is selected from the group consisting of laminin and related
peptides.
[0021] Preferably, the osmotic agent is a biologically compatible
salt such as sodium chloride or a neutral compound such as glucose,
or a zwitterionic compound such as glycine having a sufficiently
high concentration to generate, in solution, an osmotic pressure
greater than about 2000 kilopascals, preferably greater than about
3000 kilopascals.
[0022] Preferably, the agent that is transdermally delivered is a
macromolecular agent selected from the group consisting of
polypeptides, proteins, oligonucleotides, nucleic acids, and
polysaccharides.
[0023] Preferably, the polypeptides and proteins are selected from
the group selected from desmopressin, leutinizing releasing hormone
(LHRH) and LHRH analogs (e.g., goserelin, leuprolide, buserelin,
triptorelin), PTH, calcitonin, interferon-.alpha.,
interferon-.beta., interferon-.gamma., follicle stimulating hormone
(FSH), hGH, insulin, insulinotropin, and erythropoietin.
[0024] Preferably, the oligonucleotide is selected from the group
consisting of ISIS 2302, ISIS 15839 and other phosphorothiolated
oligonucleotides and other methoxyethylphosphorothiolated
oligonucleotides and the polysaccharide is selected from the group
consisting of low molecular weight heparin having a molecular
weight from 3000 to 12,000 daltons and pentosan polysulfate.
[0025] Preferably, the agent that is transdermally sampled is a
body analyte. Preferably, the body analyte is glucose.
[0026] Preferably, the agent and the anti-healing agent(s) are
delivered transdermally by passive diffusion and/or
electrotransport.
[0027] In a fourth aspect, this invention is directed to a device
for transdermally delivering an agent over a prolonged period of
time which device comprises:
[0028] (i) an element having a plurality of skin-piercing
microprotrusions for forming a plurality of microcuts through the
stratum corneum layer of the skin to form pathways through which
the agent passes; and
[0029] (ii) a reservoir comprising an agent and an amount of at
least one anti-healing agent wherein said amount of said
anti-healing agent is effective in inhibiting the decrease in said
agent transdermal flux compared to delivering said agent under
substantially identical conditions except in the absence of said
anti-healing agent(s).
[0030] In a fifth aspect, this invention is directed to a device
for transdermally sampling an agent over a prolonged period of
time, which device comprises:
[0031] (i) an element having a plurality of skin piercing
microprotusions for forming a plurality of microcuts through the
stratum corneum layer of the skin to form pathways through which
the agent passes; and
[0032] (ii) a reservoir comprising an amount of at least one
anti-healing agent wherein said amount of said anti-healing agent
is effective in inhibiting a decrease in agent transdermal flux
compared to sampling the agent under substantially identical
conditions except in the absence of said anti-healing agent(s).
[0033] In a sixth aspect, this invention is directed to a kit
transdermally delivering or sampling an agent over a prolonged
period of time comprising:
[0034] (i) a device with an array of microprotrusions for forming
microcuts through the stratum corneum layer of the skin; and
[0035] (ii) a reservoir comprising an amount of at least one
anti-healing agent wherein said amount of said anti-healing agent
is effective in inhibiting a decrease in an agent transdermal flux
compared to when the agent is delivered or sampled under
substantially identical conditions except in the absence of said
anti-healing agent.
[0036] Preferably, the anti-healing agent(s) is selected from the
group consisting of anticoagulants, anti-inflammatory agents,
agents that inhibit cellular migration, and osmotic agents in an
amount effective to generate, in solution, an osmotic pressure
greater than about 2000 kilopascals, preferably greater than about
3000 kilopascals at 20.degree. C. or mixtures thereof.
[0037] Preferably, the anticoagulant is selected from the group
consisting of heparin having a molecular weight from 3000 to 12,000
daltons, pentosan polysulfate, citric acid, citrate salts such as
sodium citrate, EDTA, and dextrans having molecular weight from
2000 to 10,000 daltons.
[0038] Preferably the anti-inflammatory agent is selected from the
group consisting of hydrocortisone sodium phosphate, betamethasone
sodium phosphate, and triamcinolone sodium phosphate.
[0039] Preferably, the agent that inhibits the cellular migration
is selected from the group consisting of laminin and related
peptides.
[0040] Preferably, the osmotic agent is a biologically compatible
salt such as sodium chloride or a neutral compound such as glucose,
or a zwitterionic compound such as glycine having a sufficiently
high concentration to generate, in solution, an osmotic pressure
greater than about 2000 kilopascals, preferably greater than about
3000 kilopascals.
[0041] Preferably, the agent that is transdermally delivered is a
macromolecular agent selected from the group consisting of
polypeptides, proteins, oligonucleotides, nucleic acids, and
polysaccharides.
[0042] Preferably, the polypeptides and proteins are selected from
the group selected from desmopressin, leutinizing releasing hormone
(LHRH) and LHRH analogs (e.g., goserelin, leuprolide, buserelin,
triptorelin), PTH, calcitonin, interferon-.alpha.,
interferon-.beta., interferon-.gamma., follicle stimulating hormone
(FSH), hGH, insulin, insulinotropin, and erythropoietin.
[0043] Preferably, the oligonucleotide is selected from the group
consisting of ISIS 2302, ISIS 15839 and other phosphorothiolated
oligonucleotides and other methoxyethylphosphorothiolated
oligonucleotides and the polysaccharide is selected from the group
consisting of low molecular weight heparin having a molecular
weight from 3000 to 12,000 daltons and pentosan polysulfate.
[0044] Preferably, the agent that is transdermally sampled is a
body analyte. Preferably, the body analyte is glucose.
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] The invention will now be described in greater detail with
reference to the accompanying drawings, wherein;
[0046] FIG. 1 is a graph of the effect of pathway closure
inhibitors on passive transdermal pentosan polysulfate flux.
[0047] FIG. 2 is a graph of the effect of pathway closure
inhibitors on passive transdermal pentosan polysulfate
delivery.
[0048] FIG. 3 is a graph of the effect of pathway closure
inhibitors on passive transdermal pentosan polysulfate flux.
[0049] FIG. 4 is a graph of the effect of pathway closure
inhibitors on passive transdermal pentosan polysulfate
delivery.
[0050] FIG. 5 is a graph of the effect of pathway closure
inhibitors on passive transdermal pentosan polysulfate
delivery.
[0051] FIG. 6 is a graph of the effect of pathway closure
inhibitors on passive transdermal pentosan polysulfate
delivery.
[0052] FIG. 7 is a graph of the effect of pathway closure
inhibitors on passive transdermal DNA delivery.
[0053] FIG. 8 is a schematic side view of a device for
transdermally delivering or sampling an agent according to the
present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0054] Definitions:
[0055] Unless stated otherwise the following terms used in this
application have the following meanings.
[0056] The term "transdermal flux" means the rate of passage of any
agent in and through the skin of an individual or the rate of
passage of any analyte out through the skin of an individual.
[0057] The term "transdermal" means the delivery or extraction of
an agent through the skin.
[0058] The term "pathway" means passages formed in the stratum
corneum of the skin by disrupting it which allow for enhanced
transdemal flux of an agent. The stratum corneum of the skin can be
disrupted by methods well known in the art such as sanding, tape
stripping, creating microcuts, and the like. Other methods are
described in U.S. Pat. Nos. 6,022,316, 5,885,211 and 5,722,397 the
disclosures of which are incorporated herein in their entirety.
Preferably the passages are formed by disrupting of the skin with a
device having a plurality of stratum corneum-piercing
microprotrusions thereby creating microcuts in the stratum
corneum
[0059] The term "microprotrusion" as used herein refers to very
tiny stratum corneum piercing elements typically having a length of
less than 500 micrometers, and preferably less than 250 micrometer,
which make a penetration in the stratum corneum. In order to
penetrate the stratum corneum, the microprotrusions preferably have
a length of at least 50 micrometers. The microprotrusions may be
formed in different shapes, such as needles, hollow needles,
blades, pins, punches, and combinations thereof.
[0060] The term "microprotrusion array" as used herein refers to a
plurality of microprotrusions arranged in an array for piercing the
stratum corneum. The microprotrusion array may be formed by etching
a plurality of blades from a thin sheet and folding each of the
blades out of the plane of the sheet to form the configuration
shown in FIG. 8. The microprotrusion array may also be formed in
other known manners, such as by connecting multiple strips having
microprotrusions along an edge of each of the strips. The
microprotrusion array may include hollow needles which inject a
liquid formulation. Examples of microprotrusion arrays are
described in U.S. Pat. No. 5,879,326 issued to Godshall, et al.,
3,814,097 issued to Ganderton, et al., 5,279,544 issued to Gross,
et al., 5,250,023 issued to Lee, et al., 3,964,482 issued to
Gerstel, et al., Reissue 25,637 issued to Kravitz, et al., and PCT
Publication Nos. WO 96/37155, WO 96/37256, WO 96/17648, WO
97/03718, WO 98/11937, WO 98/00193, WO 97/48440, WO 97/48441, WO
97/48442, WO 98/00193, WO 99/64580, WO 98/28037, WO 98/29298, and
WO 98/29365, all of which are incorporated herein by reference in
their entirety.
[0061] The term "prolonged delivery" as used herein means a period
of delivery that lasts for at least half an hour, preferably
between several hours to about 24 hours, more preferably between
about 8 and 24 hours.
[0062] The term "co-delivering" as used herein means the
anti-healing agent(s) is administered transdermally before the
agent is delivered; before and during transdermal flux of the
agent; during transdermal flux of the agent; and/or during and
after transdermal flux of the agent.
[0063] The term "co-sampling" as used herein means the anti-healing
agent(s) is administered transdermally before the agent is sampled
by transdermal flux; before and during transdermal flux of the
agent; during transdermal flux of the agent; and/or during and
after transdermal flux of the agent.
[0064] For the purposes for transdermal delivery, the term "agent"
as used herein refers to an agent, drug, compound, composition of
matter or mixture thereof which provides some pharmacological,
often beneficial, effect. It is intended in its broadest
interpretation as any pharmaceutically-acceptable substance which
may be delivered to a living organism to produce a desired, usually
beneficial, effect. In general, this includes therapeutic agents in
all of the major therapeutic fields including, but not limited to,
anti-infectives such as antibiotics and antiviral agents;
analgesics such as fentanyl, sufentanil, and buprenorphine, and
analgesic combinations; anesthetics; anorexics; antiarthritics;
antiasthmatic agents such as terbutaline; anticonvulsants;
antidepressants; antidiabetics agents; antidiarrheals;
antihistamines; antiinflammatory agents; antimigraine preparations;
antimotion sickness preparations such as scopolamine and
ondansetron; antinauseants; antineoplastics; antiparkinsonism
drugs; antipruritics; antipsychotics; antipyretics; antispasmodics
including gastrointestinal and urinary; anticholinergics;
sympathomimetrics; xanthine derivatives; cardiovascular
preparations including calcium channel blockers such as nifedipine;
betaagonists such as dobutamine and ritodrine; beta blockers;
antiarrythmics; antihypertensives such as atenolol; ACE inhibitors
such as ranitidine; diuretics; vasodilators including general,
coronary, peripheral and cerebral; central nervous systems
stimulants; cough and cold preparations; decongestants;
diagnostics; hormones such as parathyroid hormones; hypnotics;
immunosuppressives; muscle relaxants; parasympatholytics;
parasympathomimetrics; prostaglandins; proteins; peptides;
psychostimulants; vaccines, sedatives and tranquilizers.
[0065] The invention is particularly useful in the controlled
delivery of peptides, polypeptides, proteins, or other
macromolecules difficult to deliver transdermally because of their
size. These macromolecular substances typically have a molecular
weight of at least about 300 Daltons, and more typically, in the
range of about 300 to 40,000 Daltons. Examples of polypeptides and
proteins which may be delivered in accordance with the present
invention include, without limitation, LHRH, LHRH analogs (such as
goserelin, leuprolide, buserelin, triptorelin, gonadorelin,
napharelin and leuprolide), GHRH, GHRF, insulin, insulinotropin,
calcitonin, octreotide, endorphin, TRH, NT-36 (chemical name:
N-[[(s)-4-oxo-2-azetidinyl]-carbonyl]-L-histidyl-L-prolinamide),
liprecin, pituitary hormones (eg, HGH, HMG, HCG, desmopressin
acetate, etc), follicle luteoids, .alpha.-ANF, growth factor such
as releasing factor (GFRF), .beta.-MSH, GH, somatostatin,
bradykinin, somatotropin, platelet-derived growth factor,
asparaginase, bleomycin sulfate, chymopapain, cholecystokinin,
chorionic gonadotropin, corticotropin (ACTH), erythropoietin,
epoprostenol (platelet aggregation inhibitor), glucagon, hirudin
and hirudin analogs such as hirulog, hyaluronidase, interleukin-2,
menotropins (urofollitropin (FSH) and LH), oxytocin, streptokinase,
tissue plasminogen activator, urokinase, vasopressin, desmopressin,
ACTH analogs, ANP, ANP clearance inhibitors, angiotensin II
antagonists, antidiuretic hormone agonists, antidiuretic hormone
antagonists, bradykinin antagonists, CD4, ceredase, CSI's,
enkephalins, FAB fragments, IgE peptide suppressors, IGF-1,
neurotrophic factors, colony stimulating factors, parathyroid
hormone and agonists, parathyroid hormone antagonists,
prostaglandin antagonists, pentigetide, protein C, protein S, renin
inhibitors, thymosin alpha-1, thrombolytics, TNF, PTH, heparin
having a molecular weight from 3000 to 12,000 daltons, vaccines,
vasopressin antagonist analogs, interferon-.alpha., -.beta., and
-.gamma., alpha-1 antitrypsin (recombinant), and TGF-beta.
[0066] It is to be understood that more than one agent may be
incorporated into the agent formulation in the method of this
invention, and that the use of the term "agent" in no way excludes
the use of two or more such agents or drugs.
[0067] The agents can be in various forms, such as free bases,
acids, charged or uncharged molecules, components of molecular
complexes or nonirritating, pharmacologically acceptable salts.
Also, simple derivatives of the agents (such as ethers, esters,
amides, etc) which are easily hydrolyzed by body pH, enzymes, etc,
can be employed. The agents can be in solution, in suspension or a
combination of both in the drug reservoir. Alternatively, the agent
can be a particulate.
[0068] The amount of agent employed in the delivery device will be
that amount necessary to deliver a therapeutically effective amount
of the agent to achieve the desired result. In practice, this will
vary widely depending upon the particular agent, the site of
delivery, the severity of the condition, and the desired
therapeutic effect. Thus, it is not practical to define a
particular range for the therapeutically effective amount of agent
incorporated into the method.
[0069] For the purposes for transdermal sampling, the term "agent"
as used herein refers to body analytes to be sampled. The term
"analyte" as used herein means any chemical or biological material
or compound suitable for passage through a biological membrane by
the technology taught in this present invention, or by technology
previously known in the art, of which an individual might want to
know the concentration or activity inside the body. Glucose is a
specific example of an analyte because it is a sugar suitable for
passage through the skin, and individuals, for example those having
diabetes, might want to know their blood glucose levels. Other
examples of analytes include, but are not limited to, such
compounds as sodium, potassium, bilirubin, urea, ammonia, calcium,
lead, iron, lithium, salicylates, alcohol, licit substances,
illicit drugs, and the like.
[0070] The term "therapeutic" amount or rate refer to the amount or
rate of the agent needed to effect the desired pharmacological,
often beneficial, result.
[0071] The term "passive" transdermal delivery, is used herein to
describe the passage of an agent through a body surface, eg, skin
by passive diffusion. Typically, passive delivery devices have a
drug reservoir which contains a high concentration of a drug. The
device is placed in contact with a body surface for an extended
period of time, and is allowed to diffuse from the reservoir and
into the body of the patient, which has a much lower concentration
of drug. The primary driving force for passive drug delivery is the
concentration gradient of the drug across the skin. In this type of
delivery, the drug reaches the bloodstream by diffusion through the
dermal layers of the body. The preferred agents for passive
delivery are hydrophobic non-ionic agents, given that the drug must
diffuse through the lipid layers of the skin.
[0072] The term "electrotransport" is used herein to describe the
passage of a substance, eg, a drug or prodrug, through a body
surface or membrane, such as the skin, mucous membranes, or nails,
induced at least partially by the application of an electric field
across the body surface (eg, skin). A widely used electrotransport
process, iontophoresis, involves the electrically induced transport
of therapeutic agents in the form of charged ions. Ionizable
therapeutic agents, eg, in the form of a salt which when dissolved
forms charged agent ions, are preferred for iontophoretic delivery
because the charged agent ions move by electromigration within the
applied electric field. Electroosmosis, another type of
electrotransport process, involves the movement of a liquid, which
liquid contains a charged and/or uncharged therapeutic agent
dissolved therein, through a biological membrane (e.g., skin) under
the influence of an electric field. Another type of
electrotransport, electroporation, involves the formation of
transiently-existing pores in a living biological membrane by
applying high voltage pulses thereto and delivery of a therapeutic
agent therethrough. However, in any given electrotransport process,
more than one of these processes may be occurring simultaneously to
some extent. Accordingly, the term "electrotransport" is used
herein in its broadest possible interpretation to include the
electrically induced or enhanced transport of at least one agent,
which may be charged, ie, in the form of ions, or uncharged, or of
mixtures thereof, regardless of the specific mechanisms by which
the agent is actually transported.
[0073] The term "anti-healing agent" means an agent which alone or
in combination acts to prevent or diminish skin's natural healing
processes thereby preventing the closure of the pathways formed by
disruptions such as microslits/microcuts in the stratum corneum of
the skin. Examples of suitable anti-healing agents include, but are
not limited to:
[0074] (1) osmotic agents which include neutral compounds such as
glucose, salts such as sodium chloride, and zwitterionic compounds
such as amino acids.
[0075] The formulation (as is or reconstituted from a dry
formulation) should have an osmotic pressure greater than about
2000 kPa and more preferably about 3000 kPa at 20.degree. C. The
osmotic pressure being calculated from the relationship:
.PI.=iMRT
[0076] where i is the van't Hoff factor, M is the molarity of the
solute, R is the universal gas constant (8.314 J K.sup.-1
mol.sup.-1) and T the temperature in degrees Kelvin.
[0077] For neutral compounds, i is 1 and the concentration at 2000
kPa is 0.8 M; and at about 3000 kPa it is 1.2 M.
[0078] Neutral compounds include:
[0079] (a) organic solvents such as dimethylsulfoxide.
[0080] (b) acids in the neutral state such as boric acid, and the
like.
[0081] (c) ether alcohols and polymers of ethylene oxide comprising
at least one alcohol group and having a molecular weight ranging
from 92 to 500. Compounds in this group include ethoxydiglycol,
diethylene glycol, dipropylene glycol, triethylene glycol, PEG-4,
PEG-6, PEG-8 and PEG-9, and the like;
[0082] (d) aliphatic alcohols comprising two alcohol groups such as
propylene glycol and butane diol, and the like;
[0083] (e) aliphatic alcohols comprising three alcohol groups such
as glycerol, and 1,2,6-hexanetriol, and the like;
[0084] (f) tetrahydric alcohols such as erythritol and threitol,
and the like;
[0085] (g) pentahydric alcohols such as adonitol, xylitol and
arabitol, and the like;
[0086] (h) hexahydric alcohols such as sorbitol, mannitol,
galactitol, and the like;
[0087] (i) aliphatic compounds comprising one ketonic or aldehyde
group and at least two alcohol groups. Compounds in this group
include deoxyribose, ribulose, xylulose, psicose, sorbose, and the
like.
[0088] (j) cyclic polyols such as inositol, and the like;
[0089] (k) monosaccharides such as apiose, arabinose, lyxose,
ribose, xylose, digitoxose, fucose, quercitol, quinovose, rhamnose,
allose, altrose, fructose, galactose, glucose, gulose, hamamelose,
idose, mannose, tagatose, and the like;
[0090] (l) disaccharides such as sucrose, trehalose, primeverose,
vicianose, rutinose, scillabiose, cellobiose, gentiobiose, lactose,
lactulose, maltose, melibiose, sophorose, and turanose, and the
like.
[0091] For salts with i=2, the concentration of the salt at about
2000 kPa is about 0.4 M; at about 3000 kPa it is about 0.6 M. These
salts include: sodium chloride, the salt forms of acetic acid,
propionic acid, glycolic acid, pyruvic acid, hydracrylic acid,
lactic acid, pivalic acid, beta-hydroxybutyric acid, glyceric acid,
sorbic acid, mandelic acid, atrolactic acid, tropic acid, quinic
acid, glucuronic acid, gluconic acid, gulonic acid, glucoheptonic
acid, benzilic acid, ammonia, monoethanolamine, diethanolamine,
aminomethylpropanediol, tromethamine, triethanolamine,
galactosamine and glucosamine.
[0092] For salts with i=3, the concentration of the salt at about
2000 kPa is about 0.3 M; at about 3000 kPa it is about 0.4 M. These
salts include: the salt forms of phosphoric acid, malonic acid,
fumaric acid, maleic acid, succinic acid, tartronic acid,
oxaloacetic acid, malic acid, alpha-ketoglutaric acid, citramalic
acid, and tartaric acid.
[0093] For salts with i=4, the concentration of the salt at about
2000 kPa is about 0.2 M; at about 3000 kPa it is about 0.3 M. These
salts include: the salt forms of aconitic acid, citric acid and
isocitric acid.
[0094] For zwitterionic compounds, i is about 1 and the
concentration at about 2000 kPa is about 0.8 M; at about 3000 kPa
it is about 1.2 M.
[0095] Zwitterionic coumpounds include: amino acids such as
glycine, alanine, proline, threonine and valine, diamino acids such
as glycylglycine, buffers such as 4-morpholinepropane sulfonic acid
(MOPS), (2-{[tris(hydroxymethyl) methyl]amino}-1-ethane sulfonic
acid (TES), 4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid
(HEPES), .beta.-hydroxy-4-(2-hydroxyethyl)-1-piperazinepropane
sulfonic acid monohydrate (HEPPSO), tricine, bicine, CHES and CAPS
and the like.
[0096] (2) Anticoagulants such as citric acid, citrate salts (e.g.
sodium citrate), dextran sulfate sodium, EDTA, pentosan
polysulfate, oligonucleotides, aspirin, low molecular weight
heparin, and lyapolate sodium.
[0097] (3) anti-inflammatory agents such as betamethasone
21-phosphate disodium salt, triamcinolone acetonide 21-disodium
phosphate, hydrocortamate hydrochloride, hydrocortisone
21-phosphate disodium salt, methylprednisolone 21-phosphate
disodium salt, methylprednisolone 21-succinate sodium salt,
paramethasone disodium phosphate, prednisolone 21-succinate sodium
salt, prednisolone 21-m-sulfobenzoate sodium salt, prednisolone
21-diethylaminoacetate hydrochloride, prednisolone sodium
phosphate, prednylidene 21-diethylaminoacetate hydrochloride,
triamcinolone acetonide 21-disodium phosphate; the salt form of
NSAIDs such as aspirin and other salicylates, bromfenac,
diclofenac, diflunisal, etodolac, fenoprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid,
naproxen, oxaprozin, piroxicam, sulindac, tolmetin; and
antiinflammatory peptides such as antiflammin 1 and antiflammin 2;
and
[0098] (4) agents that effect cellular migration such as laminin
and related peptides and fibronectin related peptides.
[0099] The range of concentration for anticoagulant agents,
anti-inflammatory agents, and agents that inhibit cellular
migration is between 0.1 and 10% in the formulation.
MODES FOR CARRYING OUT THE INVENTION
[0100] The major barrier properties of the skin, such as resistance
to diffusion of drugs, reside with the outermost layer of the skin,
i.e., the stratum corneum. The inner division, i.e., the backing
layers, of the epidermis generally comprises three layers commonly
identified as stratum granulosum, stratum malpighii, and stratum
germinativum. There is essentially little or no resistance to
transport or to absorption of an agent through these layers.
Therefore, in order to enhance transdermal flux, the
microprotrusions used to create pathways in the body surface in
accordance with the present invention need only penetrate through
the stratum corneum in order for the agent to be transdermally
delivered or sampled with little or no resistance through the
skin.
[0101] There have been many attempts to mechanically penetrate or
disrupt the skin thereby creating pathways into the skin in order
to enhance the transdermal flux.
[0102] However, the pathways created by the microslits/microcuts
are quickly closed and sealed by the skin's natural healing
processes. Accordingly, the enhancement in transdermal agent flux
provided by these pathways is completely eliminated within several
hours of making the pathways. The present invention inhibits the
decrease in the transdermal flux of an agent due to the pathway
closure after the pathways have been made.
[0103] In one of its embodiments, the skin is treated with a
microprotusion array device to form small cuts, slits, or holes
called pathways in the outermost layer of the body surface to a
limited depth. The microprotrusions may be formed in different
shapes, such as needles, hollow needles, pins, punches, and
combinations thereof. An agent delivery or sampling reservoir is
placed in contact with the pretreated region of the body surface to
deliver or sample the agent. The agent delivery or sampling
reservoir contains an anti-healing agent(s) which is co-delivered
with the agent. This anti-healing agent prevents or at least
inhibits the pathways from closing and hence inhibits the decrease
in the transdermal flux of the agent to be delivered or sampled.
Alternatively, the anti-healing agent reservoir and the agent
delivery or sampling reservoir may be different reservoirs.
[0104] FIG. 8 illustrates a transdermal delivery or sampling patch
10 including a plurality of microprotrusions 12, a reservoir 14, an
adhesive backing layer 16, and an impermeable backing layer 18.
Although the reservoir 14 has been illustrated on a skin distal
side of the microprotrusions 12, it should be understood that the
reservoir may also be located in other positions. For example, a
reservoir 14 may be provided by a discreet layer on the skin
proximal or skin distal side of the base sheet which supports the
microprotrusions 12. The reservoir 14 may be provided by coatings
on the microprotrusions, and/or the reservoir may be provided by
coatings on the other parts of the patch 10. Although the present
invention has been described as including an agent and an
anti-healing agent, it should be understood that the agent and the
anti-healing agent may be provided in the same reservoir or
different reservoirs in the device.
[0105] The device of the present invention can be used in
connection with agent delivery, agent sampling, or both. In
particular, the device of the present invention is used in
connection with transdermal drug delivery, transdermal analyte
sampling, or both. Transdermal delivery devices for use with the
present invention include, but are not limited to, passive devices,
electrotransport devices, osmotic devices, and pressure-driven
devices. Transdermal sampling devices for use with the present
invention include, but are not limited to, passive devices, reverse
electrotransport devices, negative pressure driven devices, and
osmotic devices. The transdermal devices of the present invention
may be used in combination with other methods of increasing agent
flux, such as skin permeation enhancers.
EXAMPLES
[0106] The following preparations and examples are given to enable
those skilled in the art to more clearly understand and practice
the present invention. They should not be considered as limiting
the scope of the invention but merely as being illustrative and
representative thereof.
Example 1
[0107] Decrease in drug flux has been studied with three model
drugs presenting different charge characteristics: pentosan
polysulfate (PPS), a highly negatively charged compound, DECAD, a
synthetic model decapeptide bearing two positive charges at pH 5.5,
and inulin, a neutral polysaccharide. These compounds do not
penetrate the skin significantly without the use of penetration
enhancers or physical disruption of the skin barrier.
[0108] In this experiment, PPS, DECAD, and inulin were delivered by
passive diffusion through pathways in the skin created by
pretreatment with a microprotrusion array. Pretreatment involves
placing a microprotrusion array onto the skin with sufficient force
to create a plurality of microslits/microcuts through the stratum
corneum of the skin. The microprotrusion array is then removed from
the skin and then some form of agent delivery device or agent
reservoir is placed over the pathways in order to effect agent
delivery or sampling. Pretreatment was used instead of integrated
system because pathway closure appears to occur more rapidly and
more reproducibly following pretreatment than when the
microprotrusions are left in the skin during drug delivery. The
concentration of PPS was below the concentration required for
anticoagulant effect. All drugs were dissolved in water and
solutions were gelled with 2% hydroxyethylcellulose. Concentration
of PPS, DECAD and inulin were 0.1 mg/mL, 13 mg/mL and 2.5 mg/mL,
respectively. PPS and DECAD were radiolabeled with tritium. Insulin
was radiolabeled with .sup.14C.
[0109] In hairless guinea pigs (HGPs), the skin of one flank was
manually stretched bilaterally at the time of application of the
system. Microprotrusion array application was performed with an
impact applicator. The system applied comprised a foam double
adhesive ring (diameter 3.8 cm, thickness 0.16 cm) with a 2
cm.sup.2 reservoir in the middle containing a microprotrusion array
having an area of 2 cm.sup.2 and comprised of a stainless steel
sheet having a thickness of 0.025 mm, trapezoidally shaped blades
bent at an angle of approximately 90.degree. to the plane of the
sheet, the microprotrusions had a length of 545 micrometer, and a
microprotrusion density of 72 microprotrusions/cm.sup.2- .
Following application, the stretching tension was released. The
adhesive ring was left adhered on the skin and the microprotrusion
array was removed. The drug formulation (350 .mu.L) was dispensed
into the drug compartment and a backing membrane was applied to the
adhesive outer surface of the ring to seal the system. A total of
six HGPs were treated with the same drug formulation. At 1 hour and
24 hours after application, the systems from 3 HGPs from each group
were removed and residual drug washed from the skin. The amount of
drug that had penetrated during these time intervals was determined
by measuring urinary excretion of radioactivity for two days
following removal of the patch and corrected from the percentage
excreted following iv injection (previous studies had shown that
for .sup.3H-PPS, .sup.3H DECAD, and .sup.14C inulin, percentage
excreted over two days following injection were 32%, 65% and 94%,
respectively). The results (Table I) show that between 1 hour and
24 hour, flux decreased by at least one order of magnitude for all
drugs indicating that pathways formed by piercing of the skin by
the microprotrusions had at least partially closed.
1TABLE I Flux of model drugs following Microprotrusion array
pretreatment Drug Flux (.mu.g/(cm.sup.2h)) 1 h 24 h PPS 0.05 mg/mL
0.177 .+-. 0.039 0.015 .+-. 0.002 DECAD 12 mg/mL 1.77 .+-. 0.39
0.097 .+-. 0.035 Inulin 2.5 mg/mL 13.9 .+-. 1.6 0.489 .+-.
0.123
Example 2
[0110] Inhibition of pathway collapse by chemical agents was
studied following pretreatment of the skin with a microprotrusion
array and application of a formulation containing the agent for 24
h. Quantitation was performed by evaluation of dye impregnation of
the pathways.
[0111] In HGPs, the skin of one flank was manually stretched
bilaterally at the time of application. Application of the
microprotrusion array was performed with an impact applicator. The
system applied comprised a foam double adhesive ring (diameter 3.8
cm, thickness 0.16 cm) with a 2 cm.sup.2 reservoir in the middle
containing a microprotrusion array having an area of 2 cm.sup.2 and
comprised of a stainless steel sheet having a thickness of 0.025
mm, trapezoidally shaped blades bent at an angle of approximately
90.degree. to the plane of the sheet. The microprotrusions had a
length of 545 micrometer, and a microprotrusion density of 72
microprotrusions/cm.sup.2. Following application, the stretching
tension was released. The adhesive ring was left adhered on the
skin and the microprotrusion array was removed. A formulation (350
.mu.L) containing the tested compound in water and optionally a
gelling agent (hydroxyethylcellulose (HEC) at 2% or silica gel at
50%) was dispensed into the drug reservoir and a backing membrane
was applied to the adhesive outer surface of the ring to seal the
system. The guinea pig received a second system containing a
different formulation on the opposite site. Twenty four hours after
application, three systems from each group were removed and
residual formulation washed from the skin. The skin was stained
with a 1% methylene blue solution. Excess dye was thoroughly
removed with 70% isopropyl alcohol pads and a picture of the site
was taken. Pictures were scored on a 0 to 5 scale, 5 being the dye
uptake obtained immediately following microprotrusion array
application and 0 being the dye uptake obtained after 24 h contact
with a control formulation. A score of 0.5 or greater was
considered significant. Various osmotic agents, anticoagulants,
antiinflammatory agents, gelling agents as well as gels of
different pH and various additives were tested (Table II). Among
the osmotic agents, the most effective agents were the polyol
1,2,6-hexanetriol, glucuronic acid, the polymer of ethylene oxide
diethylene glycol, the pentahydric alcohol adonitol, the hexahydric
alcohol sorbitol, the polyol-amine tromethamine, and the
monosaccharide glucose. Among the anticoagulants, citric acid,
EDTA, as-well as dextran 5000 were the most effective agents in
preventing pathway closure. The antiinflammatory agents
betamethasone disodium phosphate as well as ketoprofen sodium salt
presented a significant effect. The keratolytic agent salicylic
acid also had an effect on pathway closure. Low pH also inhibited
pathway closure. Surfactants (anionic, cationic and nonionic), at
non-irritating concentrations, had no effect. Inert agents failed
to prevent pathway closure. Sites exposed to glycerol and citric
acid were also stained with India ink to confirm that the pathways
were open for larger sized compounds.
2TABLE II Inhibition of Pathway Closure by Chemicals as evaluated
with methylene blue following Microprotrusion array Pretreatment
Additive class Additive Concentration Score Osmotic agents
Dimethylsulfoxide 10% (1.3 M) 1.0 .+-. 0.0 Ethanol 0% (4.3 M) 0
.+-. 0 Isopropyl alcohol 30% (5 M) 0.2 .+-. 0.2 Propylene glycol
70% (9.2 M) 1.0 .+-. 0.6 50% (6.6 M) 1.3 .+-. 0.1 30% (3.9 M) 0.7
.+-. 0.2 1-3 Butane diol 50% (5.5 M) 0.2 .+-. 0.2 2-3 Butane diol
50% (5.5 M) 2.2 .+-. 0.2 1-2 Butane diol 50% (5.5 M) 2.0 .+-. 0.8
1-4 Butane diol 50% (5.5 M) 3.0 .+-. 0.3 Diethylene glycol 50% (4.7
M) 3.2 .+-. 0.2 Thiodiglycol 50% (4.1 M) 0.3 .+-. 0.3
Ethoxydiglycol 50% (3.7 M) 0.5 .+-. 0.3 Triethylene glycol 50% (3.3
M) 3.7 .+-. 0.3 30% (2 M) 3.3 .+-. 0.3 10% (0.7) 1.3 .+-. 0.3 PEG-4
50% (2.6 M) 2 .+-. 0.6 PEG-12 50% (0.9 M) 0 .+-. 0 PEG-350 50%
(0.03 M) 0 .+-. 0 Glycerin 70% (7.6 M) 2.7 .+-. 0.3 50% (5.4 M) 3.0
.+-. 0.2 30% (3.3 M) 2.7 .+-. 0.2 1,2,6-Hexanetriol 50% (3.7 M) 3.8
.+-. 0.2 23% (1.7 M) 3.0 .+-. 0.5 11% (0.8 M) 2.0 .+-. 0.3 Inositol
10% (0.6 M) 1.5 .+-. 0.3 Erythritol 30% (2.5 M) 3.3 .+-. 0.4
Adonitol 50% (3.3 M) 3.7 .+-. 0.3 23% (1.5 M) 3.5 .+-. 0.3 11% (0.7
M) 3.0 .+-. 0.3 Sorbitol 50% (2.7 M) 3.3 .+-. 0.3 23% (1.3 M) 3.3
.+-. 0.3 11% (0.6 M) 1.3 .+-. 0.6 Ribose 50% (3.3 M) 2.3 .+-. 0.3
D-Glucose 50% (2.8 M) 4.0 .+-. 0.3 23% (1.3 M) 3.5 .+-. 0.5 11%
(0.6 M) 1.8 .+-. 0.6 5% (0.3 M) 1.5 .+-. 0.0 L-Glucose 23% (1.3 M)
3.5 .+-. 0.3 Sucrose 50% (1.5 M) 1.7 .+-. 0.6 Trehalose 50% (1.5 M)
1.5 .+-. 0.0 NaCl 3.5% (0.6 M) 1.8 .+-. 0.2 Sodium acetate 4.9%
(0.6 M) 1.7 .+-. 0.1 Ammonium acetate 4.9% (0.6 M) 2.1 .+-. 0.1
Glycolic acid, 24% (2.4 M) 2.7 .+-. 0.1 sodium salt 12% (1.2 M) 2.6
.+-. 0.1 6% (0.6 M) 1.7 .+-. 0.1 Gluconic acid 30% (1.4 M) 4.5 .+-.
0.0 sodium salt 13% (0.6 M) 3.3 .+-. 0.0 10% (0.5 M) 2.7 .+-. 0.2
Glucuronic acid 13% (0.6 M) 3.0 .+-. 0.3 sodium salt 10% (0.5 M)
3.5 .+-. 0.3 5% (0.2 M) 1.0 .+-. 0.0 Ammonium chloride 3.2% (0.6 M)
2.6 .+-. 0.1 Tromethamine 50% (3.2 M) 3.7 .+-. 0.3 hydrochloride
9.5% (0.6 M) 2.3 .+-. 0.3 Galactosamine 50% (2.3 M) 2.8 .+-. 0.3
hydrochloride Malic acid, 11% (0.6 M) 2.1 .+-. 0.3 disodium salt
Tartaric acid, 12% (0.6 M) 1.5 .+-. 0.4 disodium salt Glycine 9%
(1.2 M) 1.8 .+-. 0.3 Surfactants Sodium dodecyl 0.01% 0 .+-. 0
sulfate Cetyl pyridinium 0.01% 0 .+-. 0 chloride Tween20 1% 0.2
.+-. 0.2 Inert agents Fumed silica 14% 0 .+-. 0 (Cab.O.Sil.sup.7)
Silica gel (2-25 ?m) 50% 0 .+-. 0 Hydroxyethyl- 3% 0 .+-. 0
cellulose 2% 0 .+-. 0 0.75% 0 .+-. 0 pH 4.5 0.15 M 0.8 .+-. 0.4
acetate buffer 7 0.15 M MOPS 0 .+-. 0 buffer 9 0.15 M Boric 0.3
.+-. 0.2 acid buffer Anticoagulants EDTA 5% 1.3 .+-. 0.2 Citric
acid disodium 3% 1.2 .+-. 0.2 salt 1% 0.3 .+-. 0.2 0.5% 0 .+-. 0
Dextran 5000 5% 2.2 .+-. 0.4 Oligonucleotide 5% 0.7 .+-. 0.2 (ISIS
2302) Pentosan polysulfate 5% 0.5 .+-. 0.0 0.01% 0 .+-. 0 Heparin
2% 0.3 .+-. 0.2 Antiinflammatory Betamethasone 2% 2.3 .+-. 0.4
agents phospate Na Ketoprofen Na 2% 2.3 .+-. 0.6 Calcium Calcium
chloride 2% 0.7 .+-. 0.4 supplement Actin Cytochalasin D 0.025% 1.5
.+-. 0.0 polymerization inhibitor Laminin and Laminin 0.05% 1.0
.+-. 0.3 related peptides Ser-Ile-Lys-Val- 0.05% 0.5 .+-. 0.5
Ala-Val Tyr-Ile-Gly-Ser- 0.05% 0.3 .+-. 0.3 Arg-NH.sub.2
Fibronectin Arg-Gly-Asp 1% 0.7 .+-. 0.4 related peptides
Miscellaneous Insulin 3 mM 0.2 .+-. 0.2
Example 3
[0112] Pentosan polysulfate (PPS), a highly negatively charged
compound, does not penetrate the skin significantly without the use
of penetration enhancers or physical disruption of the skin
barrier. In this experiment, PPS was delivered by passive diffusion
through pathways in the skin created by a microprotrusion array.
The concentration of PPS was below the concentration required for
inhibition of pathway collapse (see Table II). Therefore, at the
concentration used in this experiment, PPS behaved like a drug
lacking any activity on pathway closure. The purpose of the
experiment was to show that inhibitors of pathway collapse
identified in Example 2 also improved drug flux through the skin in
vivo.
[0113] In all guinea pigs, the skin of one flank was manually
stretched bilaterally at the time of the application of the system.
Microprotrusion array application was performed with an impact
applicator. The system applied comprised a foam double adhesive
ring (diameter 3.8 cm, thickness 0.16 cm) with a drug containing
hydrogel having a skin contact area of 2 cm.sup.2 in the middle
containing a microprotrusion array having an area of 2 cm.sup.2 and
comprised of a stainless steel sheet having a thickness of 0.025
mm, trapezoidally shaped blades bent at an angle of approximately
90.degree. to the plane of the sheet, the microprotrusion had a
length of 545 .mu.m, and a microprotrusion density of 72
microprotrusion/cm.sup.2. Following application, the stretching
tension was released. The adhesive ring was left adhered on the
skin and the microprotrusion array was removed. A hydrogel
containing .sup.3H-PPS in water (PPS concentration of 0.1 mg/mL, 2%
HEC, 350 .mu.L) was dispensed into the drug compartment and a
plastic cover was applied to the adhesive outer surface of the ring
to seal the system. Additional groups of HGPs were treated in the
same way, except that the formulation contained 3% citric acid
trisodium salt or 50% 1,2,6-hexanetriol. At 1 and 24 h after
application, 3 systems from each group were removed and residual
drug washed from the skin. The amount of drug penetrated during
these time intervals was determined by measuring urinary excretion
of tritium (previous studies had shown that in HGPs, 32% of the
tritium derived from .sup.3H-PPS injected intravenously is excreted
in urine). The results, as shown in FIG. 1, show that between 1
hour and 24 hours, flux decreased by about 12 fold, demonstrating
pathway closure. Citric acid and 1,2,6-hexanetriol inhibited this
decrease in flux. Flux in the presence of 1,2,6-hexanetriol was
decreased by less than 2 fold between 1 and 24 h. Total amount
transported was increased about 4 and 7 folds in the presence of
citric acid and 1,2,6-hexanetriol, respectively, as compared to
controls as shown in FIG. 2.
Example 4
[0114] A second experiment was performed with PPS. Conditions were
identical to that described in Example 3 except that the
microprotrusion array had shorter blades, length 194 micrometer,
and higher microprotrusion density (190 microprotrusion/cm.sup.2).
PPS concentration was 0.16 mg/mL and was still below the
concentration required for inhibition of pathway collapse.
Evaluation was performed at 45 min instead of 1 h. In addition,
additional groups of animals received a formulation containing the
mixture of 3% citric acid trisodium salt and 50% 1,2,6-hexanetriol.
Similarly to the precedent example, results shown in FIG. 3 show
that between 0.75 and 24 h, flux decreased dramatically,
demonstrating pathways shutdown. The additive used did not modify
the 45 min PPS flux, indication that they did not present
permeation enhancing properties and that pathways had not
significantly closed during this period. At 24 hours, citric acid
and 1,2,6-hexanetriol inhibited significantly the decrease in flux.
Flux in the presence of the mixture of citric acid trisodium salt
and 1,2,6-hexanetriol resulted in a complete inhibition of the
decrease in PPS flux observed between 45 min and 24 h. Total
amounts of PPS transported are shown in FIG. 4. The effect observed
in the presence of 3% citric acid trisodium salt and 50%
1,2,6-hexanetriol is greater than additive. This is probably the
indication that these two agents are effective on different wound
healing mechanisms (citric acid is probably preventing clot
formation while 1,2,6-hexanetriol is probably preventing another
regeneration process such as keratinocyte migration).
Example 5
[0115] An additional experiment was performed with PPS. Conditions
were identical to that described in Example 4. Gluconic acid sodium
salt, glucuronic acid sodium salt and glucose were evaluated at 0.6
M concentration with or without 3% citric acid. Similarly to the
precedent example, as shown in FIG. 5, results show that between 1
hour and 24 hours, flux decreased dramatically, demonstrating
pathways closure. At 24 hours, all compounds and combinations
significantly increased PPS flux. Total amounts of PPS transported
are shown in FIG. 6. These results support the conclusions
presented in Example 4 and demonstrate that lower concentrations of
anti-healing agents are still very effective at inhibiting
microprotrusion pathway closure.
Example 6
[0116] Feasibility studies were conducted in hairless guinea pigs
(HGPs) to determine whether passive intracutaneous delivery of a
plasmid DNA vaccine (pCMV-AYW-HBs-Mkan), which encodes for
hepatitis B surface antigen [HBsAg]), could be achieved using
Macroflux. In all guinea pigs, the skin of one flank was manually
stretched bilateraly at the time of the application of the system.
Application of the microprotrusion array was performed with an
impact applicator. The system applied comprised a foam double
adhesive ring (diameter 2.5 cm, thickness 0.08 cm) with a 1
cm.sup.2 reservoir in the middle.
[0117] One of two configurations of microprotrusion arrays were
used. Specifications of the two arrays are given in the table
below. Each configuration has a total surface area of 2 cm.sup.2
and an active total blade surface area of 1 cm.sup.2.
3 microprotrusions Type length protrusions/cm.sup.2 8-1A 545 .mu.m
72 21-10A2 430 .mu.m 190
[0118] A microprotrusion array of the selected type was adhered to
the adhesive foam and covered the bottom of the reservoir (after
application, the microprotrusion array is in contact with the
skin). Following application, the stretching tension was released
and the microprotrusion array was left in situ. A liquid
formulation (90 .mu.L) containing 3.5 mg/mL of the plasmid DNA
vaccine in buffer (TRIS 5 mM pH 7.6) was dispensed into the drug
reservoir and a backing membrane was applied to the adhesive outer
surface of the ring to seal the system. Additional HGPs were
treated in the same way, except that the formulation contained
either 1% Tween 80 or 3% citric acid trisodium salt in addition to
the plasmid DNA and the Tris buffer. At 1 hour after application,
two systems from each group were removed and residual formulation
washed from the skin. The amount of drug penetrated at that time
was determined in a 6 mm diameter full thickness skin biopsy taken
at the skin site. The biopsy was dissolved in a digestion buffer
(sodium dodecyl sulfate/proteinase K) and relevant DNA content was
evaluated by polymerase chain (PCR) reaction followed by
electrophoresis of the PCR product. A positive control group was
included which consisted of 10 .mu.g plasmid DNA injected
intradermally. Negative controls consisted of the plasmid DNA
applied on the skin without the use of a microprotrusion array. The
results demonstrated that plasmid DNA can be successfully delivered
using microprotrusion array devices under passive delivery (FIG.
7). No plasmid DNA could be detected in skin when the plasmid DNA
was applied without use of the microprotrusion array (negative
controls). Comparison between groups showed that the most efficient
formulation contained citric acid trisodium salt. At one hour, a
more than 10 fold increase in plasmid DNA delivered was observed in
the presence of citric acid trisodium salt as compared to the
control formulation. There was no significant enhancement of
plasmid DNA delivered in the formulations containing Tween 80. With
citric acid, use of the 21-10A microprotrusion array resulted in an
increase in the amount of plasmid DNA delivered, of 2.5 fold as
compared to the 8-1A microprotrusion array, which is consistent
with greater number of protrusions in the 21-10A array.
Example 7
[0119] Examples 2-6 demonstrate that drugs of interest can have
their flux enhanced by co-delivery of pathway closure inhibitors.
In particular, it was shown that compounds presenting
anticoagulants properties are effective in preventing pathway
collapse. If these compounds can prevent pathway collapse and
therefore prolong the delivery of drug molecules, it is obvious
that if they are delivered at concentrations high enough to exert
locally their anticoagulant activity, they will prolong their own
delivery. Delivery experiments with drugs presenting anticoagulant
properties have been performed in the HGP with PPS and the
phosphorothiolated oligonucleotide ISIS 2302. PPS is a drug used in
the management of inflammatory conditions such as interstitial
cystitis, and the phosphorothiolated oligonucleotide ISIS 2302 is
an antisense drug to the mRNA coding for the ICAM1 molecule and
presenting antiinflammatory properties. Both molecules are highly
negatively charged compound and do not penetrate the skin
significantly without the use of penetration enhancers or physical
disruption of the skin barrier.
[0120] With PPS at a concentration of 300 mg/mL, a total dose of
6.5 .+-.1.1 mg was delivered in 24 hours in the HGP from a 2
cm.sup.2 passive pretreatment system identical to that described in
Example 3 (application was performed manually, using a
microprotrusion array having an area of 2 cm.sup.2 and comprised of
a stainless steel sheet having a thickness if 0.025 mm,
trapezoidally shaped blades bent at an angle of approximately
90.degree. to the plane of the sheet, the microprotrusion had a
length of 430 .mu.m, and a microprotrusion density of 190
microprotrusions/cm.sup.2- ). The dose excreted in urine (2 mg) was
found to be more than 85% intact. This contrasts with oral
administration of PPS where a 300 mg daily dose presents a
bioavailability of 1 to 3% (3 to 9 mg absorbed). In addition,
following oral delivery, less than 5% of the dose absorbed was
found intact in urine, indicating that transdermal administration
of PPS using the microprotrusion array effectively bypasses the
liver.
[0121] Additional experiments were performed with PPS in order to
test alternative modes of delivery. With PPS at a concentration of
50 mg/mL, a total dose of 1.9 .+-.0.1 mg was delivered in 4 hours
by electrotransport with a current of 100 .mu.A/cm.sup.2 and a
microprotrusion array having an area of 2 cm.sup.2 and comprised of
a stainless steel sheet having a thickness of 0.025 mm,
trapezoidally shaped blades bent at an angle of approximately
90.degree. to the plane of the sheet, the microprotrusions had a
length of 480 .mu.m, and a microprotrusion density of 241
microprotrusion/cm.sup.2. By comparison, with the same
microprotrusion array and the same PPS concentration, total dose
from a transdermal microprotrusion array with integrated drug
reservoir and a pretreatment with a microprotrusion array and
subsequent application of a drug reservoir was 2.2.+-.0.2 mg and
1.4 .+-.0.2 mg, respectively. Collectively, these results
demonstrate that PPS can be effectively delivered through the skin
for extended periods of time probably as a result of its
anticoagulant properties.
[0122] The phosphorothiolated oligonucleotide ISIS 2302 was
delivered for 24 hours using a microprotrusion array with an area
of 2 cm.sup.2, microprotrusion lengths of 480 .mu.m and 241
microprotrusions/cm.sup.2. The effect of drug concentration,
microprotrusion array pretreatment versus integrated treatment and
delivery passive versus electrotransport were evaluated. Results,
summarized in Table III, demonstrate that this compound can be
effectively delivered through the skin for extended periods of
time, probably as a result of its anticoagulant properties.
4TABLE III Transdermal Delivery of ISIS 2302 Total dose delivered
(mg) Drug Microprotrusion Pretreatment Integrated Treatment conc.
Electro- Electro- (mg/mL) Passive transport Passive transport 5
0.17 .+-. 0.02 0.47 .+-. 0.05 0.20 .+-. 0.04 0.35 .+-. 0.05 50 2.6
.+-. 0.7 6.4 .+-. 0.5 7.4 .+-. 1.5 8.3 .+-. 1.4 200 10.0 .+-. 1.9
15.6 .+-. 3.8 14.0 .+-. 3.2 15.2 .+-. 1.8
[0123] Drugs of interest that could be delivered at therapeutic
levels using the microprotrusion technology during extended periods
of time (i.e. 24 hours) and without the help of adjuvant that
prevent pathway collapse include all compounds presenting
anticoagulants properties during local delivery and having a
molecular weight greater than about 2000. These compounds include
pentosan polysulfate, oligonucleotides, low molecular weight
heparin, hirudin and hirudin analogs such as hirulog. It will be
appreciated by those of ordinary skill in the art that the
invention can be embodied in other specific forms without departing
from the spirit or essential character thereof. The presently
disclosed embodiments are therefore considered in all respects to
be illustrative and not restrictive. The scope of the invention as
indicated by the appended claims rather than the foregoing
description, and all changes which come within the meaning and
range of equivalence thereof are intended to be embraced
therein.
* * * * *